Method and apparatus for synchronizing neural stimulation to cardiac cycles

ABSTRACT

A neural stimulator senses a reference signal indicative of cardiac cycles each including a predetermined type timing reference event using a sensor external to the heart and blood vessels. The delivery of the neural stimulation pulses are synchronized to that timing reference event. Examples of the timing reference event include a predetermined cardiac event such as a P-wave or an R-wave detected from a subcutaneous ECG signal, a predetermined type heart sound detected from an acoustic signal, and a peak detected from a hemodynamic signal related to blood flow or pressure.

FIELD OF THE INVENTION

This document generally relates to neural stimulation systems andparticularly to a system providing for synchronization of neuralstimulation to cardiac cycles.

BACKGROUND

The heart is the center of a person's circulatory system. The leftportions of the heart draw oxygenated blood from the lungs and pump itto the organs of the body to provide the organs with their metabolicneeds for oxygen. The right portions of the heart draw deoxygenatedblood from the body organs and pump it to the lungs where the blood getsoxygenated. These pumping functions are accomplished by cycliccontractions of the myocardium (heart muscles). Each cycle, known as thecardiac cycle, includes systole and diastole. During systole, the heartejects blood. During diastole, the heart is filled with blood for thenext ejection (systolic) phase, and the myocardial tissue is perfused.In a normal heart, the sinoatrial node generates electrical impulsescalled action potentials. The electrical impulses propagate through anelectrical conduction system to various regions of the heart to excitethe myocardial tissue of these regions. Coordinated delays in thepropagations of the action potentials in a normal electrical conductionsystem cause the various portions of the heart to contract in synchronyto result in efficient pumping functions indicated by a normalhemodynamic performance. A blocked or otherwise abnormal electricalconduction and/or deteriorated myocardial tissue result in systolicdysfunction—because the myocytes do not contract in unison—and diastolicdysfunction—because the myocytes do not relax in unison. Decreasedsystolic and diastolic performance each contribute to a poor overallhemodynamic performance, including a diminished blood supply to theheart and the rest of the body.

The hemodynamic performance is modulated by neural signals in portionsof the autonomic nervous system. For example, the myocardium isinnervated with sympathetic and parasympathetic nerves. Activities inthese nerves, including artificially applied electrical stimuli,modulate the heart rate and contractility (strength of the myocardialcontractions). Electrical stimulation applied to the sympathetic nervesis known to increase the heart rate and the contractility, shorteningthe systolic phase of a cardiac cycle, and lengthening the diastolicphase of the cardiac cycle. Electrical stimulation applied to theparasympathetic nerves is known to have essentially the oppositeeffects.

The ability of the electrical stimulation of the autonomic nerves inmodulating the heart rate and contractility is utilized to treatabnormal cardiac conditions, such as to control myocardial remodelingand to prevent arrhythmias following myocardial infarction. It isobserved that the effects of such electrical stimulation are dependenton timing of the delivery of electrical stimuli in relation to thecardiac cycle. Thus, it is desirable to synchronize the delivery of theelectrical stimuli to the cardiac cycle. Because the electrical stimuliare delivered to portions of nerves external to the heart, there is aneed for detecting a timing reference signal for synchronizing thedelivery of the electrical stimuli to the cardiac cycle withoutintracardiac sensing.

SUMMARY

A neural stimulator senses a reference signal indicative of cardiaccycles each including a predetermined type timing reference event usinga sensor external to the heart and blood vessels. The delivery of theneural stimulation pulses are synchronized to that timing referenceevent.

In one embodiment, a neural stimulation system includes a stimulationoutput circuit, a reference signal sensor, a reference event detectioncircuit, and a stimulation control circuit. The stimulation outputcircuit delivers neural stimulation pulses. The reference signal sensorsenses a reference signal indicative of cardiac cycles each including apredetermined type timing reference event. The reference signal sensormay be placed in a site external to the circulatory system. Thereference event detection circuit detects the predetermined type timingreference event. The stimulation control circuit controls the deliveryof the neural stimulation pulses and includes a synchronization module.The synchronization module synchronizes the delivery of the neuralstimulation pulses to the predetermined type timing reference event.

In one specific embodiment, the neural stimulation system includes astimulation output circuit, one or more electrodes, a cardiac eventdetection circuit, and a stimulation control circuit. The stimulationoutput circuit delivers neural stimulation pulses. The one or moreelectrodes sense an electrocardiographic (ECG) signal. The cardiac eventdetection circuit detects predetermined type cardiac events from the ECGsignal. The stimulation control circuit controls the delivery of theneural stimulation pulses and includes a synchronization module. Thesynchronization module synchronizes the delivery of the neuralstimulation pulses to the predetermined type cardiac events.

In another specific embodiment, the neural stimulation system includes astimulation output circuit, an acoustic sensor, a heart sound detectioncircuit, and a stimulation control circuit. The stimulation outputcircuit delivers neural stimulation pulses. The implantable acousticsensor senses an acoustic signal indicative of heart sounds. The heartsound detection circuit detects predetermined type heart sounds usingthe acoustic signal. The stimulation control circuit controls thedelivery of the neural stimulation pulses and includes a synchronizationmodule. The synchronization module synchronizes the delivery of theneural stimulation pulses to the predetermined type heart sounds.

In another specific embodiment, the neural stimulation system includes astimulation output circuit, a hemodynamic sensor, a hemodynamic eventdetection circuit, and a stimulation control circuit. The stimulationoutput circuit delivers neural stimulation pulses. The hemodynamicsensor senses a hemodynamic signal. The hemodynamic event detectioncircuit detects a predetermined type hemodynamic event using thehemodynamic signal. The stimulation control circuit controls thedelivery of the neural stimulation pulses and includes a synchronizationmodule. The synchronization module synchronizes the delivery of theneural stimulation pulses to the predetermined type hemodynamic event.

In one embodiment, a method for neural stimulation is provided. A timingreference signal is sensed using a reference signal sensor placedexternal to the circulatory system. The timing reference signal isindicative of cardiac cycles each including a predetermined type timingreference event. The predetermined type timing reference event isdetected from the reference signal. A delivery of neural stimulationpulses is synchronized to the detected timing reference event.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the invention will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof. The scope of the presentinvention is defined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not necessarily drawn to scale, like numeralsdescribe similar components throughout the several views. The drawingsillustrate generally, by way of example, but not by way of limitation,various embodiments discussed in the present document.

FIG. 1 is an illustration of an embodiment of a neural stimulationsystem and portions of an environment in which the neural stimulationsystem is used.

FIG. 2 is a block diagram illustrating an embodiment of a circuit of acardiac cycle-synchronized neural stimulation system.

FIG. 3 is a block diagram illustrating a specific embodiment of thecircuit of FIG. 2.

FIG. 4 is a block diagram illustrating an embodiment of a circuit usinga wireless ECG to synchronize neural stimulation to cardiac cycles.

FIG. 5 is an illustration of an embodiment of an electrode system forsubcutaneous ECG sensing.

FIG. 6 is a block diagram illustrating an embodiment of a circuit usingheart sounds to synchronize neural stimulation to cardiac cycles.

FIG. 7 is a block diagram illustrating an embodiment of a circuit usinga hemodynamic signal to synchronize neural stimulation to cardiaccycles.

FIG. 8 is a flow chart illustrating an embodiment of a method forsynchronizing neural stimulation to cardiac cycles.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that the embodiments may be combined, or that otherembodiments may be utilized and that structural, logical and electricalchanges may be made without departing from the scope of the presentinvention. The following detailed description provides examples, and thescope of the present invention is defined by the appended claims andtheir legal equivalents.

It should be noted that references to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.

This document discusses a neural stimulation system that synchronizesthe delivery of neural stimulation pulses to cardiac cycles. The neuralstimulation system includes an implantable neural stimulator that sensesa reference signal indicative of cardiac cycles each including apredetermined type timing reference event using an implantable referenceevent sensor. The implantable reference event sensor is an extracardiacand extravascular sensor, i.e., a sensor that is placed external to apatient's circulatory system including the heart and blood vessels. Thedelivery of the neural stimulation pulses are synchronized to the timingreference event. Examples of the reference signal include a wirelessECG, an acoustic signal indicative of heart sounds, and a hemodynamicsignal.

In this document, “Surface ECG” refers to a cardiac electrical signalsensed with electrodes attached onto the exterior surface of the skin.“Wireless ECG” refers to a signal approximating the surface ECG,acquired without using surface (non-implantable, skin contact)electrodes. “Subcutaneous ECG” is a form of wireless ECG and includes acardiac electrical signal sensed through electrodes implanted insubcutaneous tissue, such as through electrodes incorporated onto animplantable medical device that is subcutaneously implanted. Asreflected in their corresponding morphologies, the surface ECG resultsfrom electrical activities of the entire heart. The wireless ECG,including but not being limited to the subcutaneous ECG, has amorphology that approximates that of the surface ECG and reflectselectrical activities of a substantial portion of the heart, up to theentire heart.

In this document, an “acoustic signal” includes any signal indicative ofheart sounds. “Heart sounds” include audible mechanical vibrationscaused by cardiac activity that can be sensed with a microphone andaudible and inaudible mechanical vibrations caused by cardiac activitythat can be sensed with an accelerometer. Known type heart soundsinclude the “first heart sound” or S1, the “second heart sound” or S2,the “third heart sound” or S3, the “fourth heart sound” or S4, and theirvarious sub-components. S1 is known to be indicative of, among otherthings, mitral valve closure, tricuspid valve closure, and aortic valveopening. S2 is known to be indicative of, among other things, aorticvalve closure and pulmonary valve closure. S3 is known to be aventricular diastolic filling sound often indicative of certainpathological conditions including heart failure. S4 is known to be aventricular diastolic filling sound resulted from atrial contraction andis usually indicative of pathological conditions. The term “heart sound”hereinafter refers to any heart sound (e.g., S1) and any componentsthereof (e.g., MI component of S1, indicative of Mitral valve closure).

In this document, a “hemodynamic signal” includes a signal providing formonitoring, calculation, or estimation of one or more measures ofhemodynamic performance such as blood pressure or pressure-relatedparameters, cardiac output, stroke volume, volume of blood flow, changein (e.g., derivative of) the volume of blood flow, and/or velocity ofblood flow.

FIG. 1 is an illustration of an embodiment of a neural stimulationsystem 100 and portions of an environment in which system 100 is used.System 100 includes implantable medical device 110 that delivers neuralstimulation pulses through leads 106 and 108, an external system 120,and a telemetry link 125 providing for communication between implantablemedical device 110 and external system 120. For illustrative purposeonly, FIG. 1 shows that lead 106 includes an electrode 107 coupled to anerve 102 of the sympathetic nervous system, and lead 108 includes anelectrode 109 coupled a nerve 104 of the parasympathetic nervous system.Nerves 102 and 104 innervate a heart 101. In various embodiments,implantable medical device 110 provides neural stimulation to any one ormore nerves through one or more leads for modulating one or morefunctions of the circulatory system including heart 101. Such leadsinclude implantable neural leads each including at least one electrodefor sensing neural activities and/or delivering neural stimulationpulses. One example of such an electrode includes a cuff electrode forplacement around an aortic, carotid, or vagus nerve.

Implantable medical device 110 delivers the neural stimulation pulsesand includes a cardiac cycle-synchronized neural stimulation circuit130. Cardiac cycle-synchronized neural stimulation circuit 130 detects apredetermined type timing reference event from a cardiac cycle andsynchronizes the delivery of neural stimulation pulses to that timingreference event. In one embodiment, cardiac cycle-synchronized neuralstimulation circuit 110 starts a predetermined offset time interval upondetection of the timing reference event and delivers a burst of neuralstimulation pulses when the offset time interval expires. In oneembodiment, implantable medical device 110 is capable of monitoringphysiologic signals and/or delivering therapies in addition to theneural stimulation. Examples of such additional therapies includecardiac pacing therapy, cardioversion/defibrillation therapy, cardiacresynchronization therapy, cardiac remodeling control therapy, drugtherapy, cell therapy, and gene therapy. In various embodiments,implantable medical device 110 delivers the neural stimulation incoordination with one or more such additional therapies.

External system 120 provides for control of and communication withimplantable medical device 110 by a physician or other caregiver. In oneembodiment, external system 120 includes a programmer. In anotherembodiment, external system 120 is a patient management system includingan external device communicating with implantable medical device 110 viatelemetry link 125, a remote device in a relatively distant location,and a telecommunication network linking the external device and theremote device. The patient management system allows access toimplantable medical device 110 from a remote location, for purposes suchas monitoring patient status and adjusting therapies. In one embodiment,telemetry link 125 is an inductive telemetry link. In an alternativeembodiment, telemetry link 125 is a far-field radio-frequency (RF)telemetry link. Telemetry link 125 provides for data transmission fromimplantable medical device 110 to external system 120. This includes,for example, transmitting real-time physiological data acquired byimplantable medical device 110, extracting physiological data acquiredby and stored in implantable medical device 110, extracting patienthistory data such as occurrences of arrhythmias and therapy deliveriesrecorded in implantable medical device 110, and/or extracting dataindicating an operational status of implantable medical device 110(e.g., battery status and lead impedance). Telemetry link 125 alsoprovides for data transmission from external system 120 to implantablemedical device 110. This includes, for example, programming implantablemedical device 110 to acquire physiological data, programmingimplantable medical device 110 to perform at least one self-diagnostictest (such as for a device operational status), and/or programmingimplantable medical device 110 to deliver one or more therapies and/orto adjust the delivery of one or more therapies.

FIG. 2 is a block diagram illustrating an embodiment of a circuit of acardiac cycle-synchronized neural stimulation system 231. System 231includes a reference signal sensor 215 and cardiac cycle-synchronizedneural stimulation circuit 130.

Reference signal sensor 215 senses a reference signal indicative ofcardiac cycles each including a predetermined type timing referenceevent. In one embodiment, reference signal sensor 215 is an implantablereference signal sensor. The timing reference event is a recurringfeature of the cardiac cycle that is chosen to be a timing reference towhich the neural stimulation is synchronized. In one embodiment,reference signal sensor 215 is configured for extracardiac andextravascular placement, i.e., placement external to the heart and bloodvessels. Examples of reference signal sensor 215 include a set ofelectrodes for sensing a subcutaneous ECG signal, an acoustic sensor forsensing an acoustic signal indicative of heart sounds, and a hemodynamicsensor for sensing a hemodynamic signal indicative of hemodynamicperformance. In one embodiment, implantable medical device 110 has animplantable housing that contains both a reference signal sensor 215 andcardiac cycle-synchronized neural stimulation circuit 130. In anotherembodiment, reference signal sensor 215 is incorporated onto the housingof implantable medical device 110. In another embodiment, referencesignal sensor 215 is electrically connected to implantable medicaldevice 110 through one or more leads. In another embodiment, referencesignal sensor 215 is communicatively coupled to implantable medicaldevice 110 via an intra-body telemetry link.

Cardiac cycle-synchronized neural stimulation circuit 130 includes astimulation output circuit 232, a reference event detection circuit 234,and a stimulation control circuit 236. Reference event detection circuit234 receives the reference signal from reference signal sensor 215 anddetects the timing reference event from the reference signal.Stimulation control circuit 236 controls the delivery of the neuralstimulation pulses and includes a synchronization module 238.Synchronization module 238 receives a signal indicative of the detectionof each timing reference event and synchronizes the delivery of theneural stimulation pulses to the detected timing reference event.Stimulation output circuit 232 delivers neural stimulation pulses uponreceiving a pulse delivery signal from stimulation control circuit 236.

FIG. 3 is a block diagram illustrating an embodiment of a circuit of acardiac cycle-synchronized neural stimulation system 331, which is aspecific embodiment of system 231. System 331 includes reference signalsensor 215 and a cardiac cycle-synchronized neural stimulation circuit330, which is a specific embodiment of cardiac cycle-synchronized neuralstimulation circuit 130. Cardiac cycle-synchronized neural stimulationcircuit 330 includes stimulation output circuit 232, a reference eventdetection circuit 334, and a stimulation control circuit 336.

Reference event detection circuit 334 is a specific embodiment ofreference event detection 234 and includes a signal processor 342 and anevent detector 344. Signal processor 342 receives the reference signalsensed by reference signal sensor 215 and processes the reference signalin preparation for the detection of the timing reference events by eventdetector 344. Event detector 344 includes a comparator having an inputto receive the processed reference signal, another input to receive adetection threshold, and an output producing a detection signalindicating a detection of the timing reference signal. In oneembodiment, signal processor 342 processes the reference signal toprovide for extraction of the timing reference event based on a singlecardiac cycle. In one specific embodiment, signal processor 342 includesa filter having a pass-band corresponding to a frequency range of thetiming reference event to prevent unwanted activities in the referencesignal from being detected by event detector 344. In another specificembodiment, signal processor 342 includes a blanking period generator togenerate a blanking period that blanks the unwanted activities in thereference signal. This approach is applied when an approximate timingrelationship between the timing reference event and the unwantedactivities, or an approximate timing relationship between anotherdetectable event and the unwanted activities, is predictable. In anotherspecific embodiment, the blanking period generator generates a blankingperiod that blanks cardiac pacing artifacts in the reference signal,i.e., unwanted activities caused by delivery of cardiac pacing pulses.In another specific embodiment, signal processor 342 includes a timinginterval generator to generate a timing interval between an intermediateevent and the timing reference event. This approach is applied when theintermediate event is more easily detectable than the timing referenceevent and when an approximate timing relationship between theintermediate event and the timing reference event is predictable. Inanother embodiment, signal processor 342 processes the reference signalto provide for extraction of the timing reference event based on aplurality of cardiac cycles. In one specific embodiment, signalprocessor 342 includes a signal averaging circuit that averages thereference signal over a predetermined number of cardiac cycles beforethe detection of the timing reference event by event detector 344.

Stimulation control circuit 336 is a specific embodiment of stimulationcontrol circuit 236 and includes a synchronization circuit 338, anoffset interval generator 339, and a pulse delivery controller 340.Synchronization circuit 338 includes one or both of a continuoussynchronization module 346 and a periodic synchronization module 348.Continuous synchronization module 346 synchronizes the delivery of theneural stimulation pulses to the timing reference event of consecutivecardiac cycles. Periodic synchronization module 348 synchronizes thedelivery of the neural stimulation pulses to the timing reference eventof selected cardiac cycles on a periodic basis. Offset intervalgenerator 339 produces an offset interval starting with the detectedtiming reference event. Pulse delivery controller 340 sends the pulsedelivery signal to start a delivery of a burst of a plurality of neuralstimulation pulses when the offset interval expires. In one embodiment,pulse delivery controller 340 sends the pulse delivery signal after thedetection of the timing reference event for each of consecutive cardiaccycles. In another embodiment, pulse delivery controller 340 sends thepulse delivery signal after the detection of the timing reference eventfor selected cardiac cycles according to a predetermined pattern orschedule, such as on a periodic basis.

FIG. 4 is a block diagram illustrating an embodiment of a cardiaccycle-synchronized neural stimulation system 431, which is a specificembodiment of system 231 and uses a wireless ECG to synchronize neuralstimulation to cardiac cycles. System 431 includes ECG electrodes 415and a cardiac cycle-synchronized neural stimulation circuit 430, whichis a specific embodiment of cardiac cycle-synchronized neuralstimulation circuit 230. Cardiac cycle-synchronized neural stimulationcircuit 430 includes stimulation output circuit 232, a cardiac eventdetection circuit 434, an arrhythmia detection circuit 452, a cardiacparameter measurement circuit 454, and a stimulation control circuit436.

In one embodiment, ECG electrodes 415 include surface ECG electrodes. Inanother embodiment, ECG electrodes 415 include electrodes for sensing awireless ECG signal. In one embodiment, ECG electrodes 415 includesubcutaneous electrodes for sensing a subcutaneous ECG signal. In oneembodiment, the subcutaneous electrodes are incorporated onto theimplantable medical device 110, which is to be subcutaneously implanted.Examples of such subcutaneous electrodes are discussed below withreference to FIG. 5. In one embodiment, at least one subcutaneouselectrode is placed in a selected location in the body near the base ofthe heart to allow selective detection of atrial depolarizations(P-waves). In another embodiment, multiple subcutaneous electrodes areplaced near base and apex of the heart to allow P-wave detection bysubtracting out unwanted activities including ventriculardepolarizations (R-waves). This approach applies when it is difficult toisolate P-waves by selecting electrode sites and filtering. At least onesubcutaneous electrode is placed near the apex of the heart to allowdetection of R-waves. The detected R-waves are then used to isolate, bysubtraction, P-waves from a subcutaneous ECG signal that includes bothP-waves and R-waves.

Cardiac event detection circuit 434 is a specific embodiment ofreference event detection circuit 234. In one embodiment, cardiac eventdetection circuit 434 includes a signal processor such as signalprocessor 342 and an event detector such as event detector 344. Thesignal processor includes a wireless ECG sensing circuit to amplify andfilter the subcutaneous ECG signal sensed through ECG electrodes 415. Anexample of electrodes and a circuit for sensing wireless ECG signalsincluding subcutaneous ECG signals is discussed in U.S. patentapplication Ser. No. 10/795,126, entitled “WIRELESS ECG IN IMPLANTABLEDEVICES,” filed on Mar. 5, 2004, assigned to Cardiac Pacemakers, Inc.,which is incorporated herein by reference in its entirety. In oneembodiment, as illustrated in FIG. 4, the timing reference event is aP-wave. Cardiac event detection circuit 434 includes a P-wave detector450 to detect P-waves from the wireless ECG signal. In one specificembodiment, P-wave detector 450 includes a filter having a pass-bandcorresponding to a frequency range of P-waves. In another specificembodiment, P-wave detector 450 includes an R-wave detector to detectR-waves from one subcutaneous signal and a blanking period generator togenerate blanking periods to blank unwanted activities including theR-waves in another wireless ECG signal. In another specific embodiment,P-wave detector 450 includes an R-wave detector to detect R-waves fromthe subcutaneous signal and a timing interval generator to generate atiming interval upon detection of each R-wave. A P-wave is estimated tooccur at the end of the timing interval.

Arrhythmia detection circuit 452 and cardiac parameter measurementcircuit 454 provide for control of neural stimulation based on cardiacconditions. Arrhythmia detection circuit 452 detects one or more typesof arrhythmia from the wireless ECG signal. Cardiac parametermeasurement module 454 measures one or more cardiac parameters such as aheart rate and an atrioventricular interval from the wireless ECGsignal.

Stimulation control circuit 436 is a specific embodiment of stimulationcontrol circuit 336 and includes a synchronization module 438.Synchronization module 438 synchronizes the delivery of the neuralstimulation pulses to the detected cardiac events such as P-waves. Inone embodiment, stimulation control circuit 436 includes elementscorresponding to those of stimulation circuit 336, including offsetinterval generator 339 and pulse delivery controller 340.Synchronization circuit 438 includes one or both of a continuoussynchronization module to synchronize the delivery of the neuralstimulation pulses to the P-wave of each of consecutive cardiac cyclesand a periodic synchronization module to synchronize the delivery of theneural stimulation pulses to the P-wave of each of selected cardiaccycles on a periodic basis. The offset interval generator produces anoffset interval starting with each detected P-wave. The pulse deliverycontroller sends the pulse delivery signal to start a delivery of aburst of a plurality of neural stimulation pulses when the offsetinterval expires. In one embodiment, the pulse delivery controller sendsthe pulse delivery signal after the detection of the P-wave for each ofconsecutive cardiac cycles. In another embodiment, the pulse deliverycontroller sends the pulse delivery signal after the detection of theP-wave for each of selected cardiac cycles according to a predeterminedpattern or schedule, such as on a periodic basis.

In one embodiment, stimulation control circuit 436 also controls thedelivery of the neural stimulation pulses based on the cardiac rhythmdetected by arrhythmia detection circuit 452 and/or the cardiacparameters measured by cardiac parameter measurement circuit 454. In oneembodiment, stimulation control circuit 436 withholds or adjusts thedelivery of the neural stimulation pulses when an arrhythmia isdetected. In another embodiment, stimulation control circuit 436 starts,stops, or adjusts the delivery of the neural stimulation pulses based onthe measured cardiac parameter, such as the heart rate and theatrioventricular interval.

FIG. 5 is an illustration of an embodiment of an electrode system forsensing one or more subcutaneous ECG signals. An electrode system forsubcutaneous ECG sensing includes two or more implantable electrodes.These implantable electrodes are selected from the electrodes including,but not being limited to, those illustrated in FIG. 5. The electrodesare selected to allow for sensing electrical activities from asubstantial portion of the heart, up to the entire heart. FIG. 5 showsan implantable medical device 510, which is a specific embodiment ofimplantable medical device 110, and electrodes incorporated onto thatdevice. Implantable medical device 510 is to be subcutaneously implantedin a patient in need of neural stimulation to modulate cardiacfunctions. In one embodiment, ECG electrodes 415 include one or moreelectrodes shown in FIG. 5. In another embodiment, in addition to one ormore electrodes shown in FIG. 5, ECG electrodes 415 include one or moreelectrodes each electrically connected to implantable medical device 510through a lead.

Implantable medical device 510 includes a hermetically sealed can 511 tohouse its circuit. Can 511 has an outer surface subject to contact withbody tissue. Can 511 includes or provides for a base of a can electrode514 that is selectable as one of the electrodes for sensing asubcutaneous ECG signal. At least a portion of the outer surface of can511 is made of electrically conductive material. In one embodiment, can511 is used as can electrode 514. In one specific embodiment, canelectrode 514 includes at least one conductive portion of can 511. Inanother embodiment, can electrode 514 is incorporated onto the outersurface of can 511 and is electrically insulated from any conductiveportion of can 511 using a non-conductive layer. In one specificembodiment, a hermetically sealed feedthrough including a conductorprovides for an electrical connection between can electrode 514 and thecircuit housed in can 511.

A header 512 is attached to can 511 and includes connectors providingfor electrical access to the circuit housed in can 511. In oneembodiment, one or more of header electrodes 516A-B are incorporatedinto the header. Header electrodes 516A-B are each selectable as one ofthe electrodes for sensing a subcutaneous ECG signal.

In one embodiment, two or more concentric electrodes 517A-C areincorporated onto the outer surface of can 511. Each of the concentricelectrodes 517A-C is selectable as one of the electrodes for sensing asubcutaneous ECG signal. Concentric electrodes 517A-C are insulated fromthe conductive portion of can 511 with a non-conductive layer andconnected to the circuit housed in can 511 via hermetically sealedfeedthroughs. In one embodiment, two electrodes, including an innerelectrode and an outer electrode, are selected from concentricelectrodes 517A-C for the wireless ECG sensing. In one embodiment, theouter electrode has a ring shape. In another embodiment, the outerelectrode has a shape approaching the contour of can 511.

In one embodiment, implantable medical device 510 includes an antenna513 used for a far-field RF telemetry link providing for communicationbetween implantable medical device 510 and external system 120. Antenna513 is electrically connected to the circuit housed in can 511. In oneembodiment, antenna 513 projects from header 512 and extends along oneside of can 511. In one embodiment, antenna 513 includes a metalconductor with a distal portion exposed for functioning as an antennaelectrode 518, which is selectable as one of the electrodes for sensinga subcutaneous ECG signal.

It is to be understood that the electrodes illustrated in FIG. 5 areintended to be examples but not limitations. Other electrodeconfigurations are usable as long as they provide for sensing of surfaceECG signals or signals that approximate the surface ECG or otherwiseallows for detection of a timing reference signal for synchronizing thedelivery of neural stimulation pulses to cardiac cycles. In variousembodiments in which multiple subcutaneous ECG vectors are sensed,multiple pairs of electrodes are selected, simultaneously or one at atime, for a multi-channel (multi-vector) subcutaneous ECG sensing. Inone specific embodiment, one or more of subcutaneous ECG vectors aresensed to approximate one or more vectors of a standard multi-leadsurface ECG recording. In another specific embodiment, multiplesubcutaneous ECG vectors are sensed based on needs of specificinformation for synchronizing the delivery of neural stimulation pulsesto cardiac cycles. Such subcutaneous ECG vectors do not necessarilyapproximate standard surface ECG vectors. In one specific embodiment,implantable medical device 510 includes header electrodes 516A-B and canelectrode 514 for the subcutaneous ECG sensing. Implantable medicaldevice 510 is programmable for sensing subcutaneous ECG vectors between(1) header electrodes 516A and 516B, (2) header electrode 516A and canelectrode 514, and/or (3) header electrode 516B and can electrode 514.In another specific embodiment, implantable medical device 510 includesone of header electrodes 516A-B, antenna electrode 518, and canelectrode 514 for the subcutaneous ECG sensing. Implantable medicaldevice 510 is programmable for sensing subcutaneous ECG vectors between(1) header electrode 516A or 516B and antenna electrode 518, (2) headerelectrode 516A or 516B and can electrode 514, and/or (3) antennaelectrode 518 and can electrode 514. In another specific embodiment,implantable medical device 510 includes header electrodes 516A-B,antenna electrode 518, and can electrode 514 for the subcutaneous ECGsensing. Implantable medical device 510 is programmable for sensingsubcutaneous ECG vectors between (1) header electrodes 516A and 518, (2)header electrode 516A and antenna electrode 518, (3) header electrode516A and can electrode 514, (4) header electrode 516B and antennaelectrode 518, (5) header electrode 516B and can electrode 514, and/or(6) antenna electrode 518 and can electrode 514. Other specificembodiments involving any electrode combinations for the subcutaneousECG sensing will be employed based on needs and consideration forsynchronizing the delivery of neural stimulation pulses to cardiaccycles as well as needs and considerations for performing otherdiagnostic and/or therapeutic functions provided by implantable medicaldevice 510.

The selection of subcutaneous ECG vectors depends on the purpose for thesubcutaneous ECG sensing. When the subcutaneous ECG signal is sensed fordetecting P-waves, the subcutaneous ECG vector that provide for areliable P wave detection are selected. When the subcutaneous ECG signalis sensed for detecting R-waves, one or more subcutaneous ECG vectorsthat provide for a reliable R wave detection are selected. In oneembodiment, when more than one subcutaneous ECG vector provides for areliable sensing for a particular purpose, the subcutaneous ECG vectorshowing the highest signal-to-noise ratio (SNR) for that purpose isselected. For example, if the subcutaneous ECG is sensed for detecting Pwaves, the subcutaneous ECG vector showing the highest SNR with P wavesbeing considered as the signal that is selected.

FIG. 6 is a block diagram illustrating an embodiment of a cardiaccycle-synchronized neural stimulation system 631, which is a specificembodiment of system 231 and uses heart sounds to synchronize neuralstimulation to cardiac cycles. System 631 includes an acoustic sensor615 and a cardiac cycle-synchronized neural stimulation circuit 630,which is a specific embodiment of cardiac cycle-synchronized neuralstimulation circuit 230. Cardiac cycle-synchronized neural stimulationcircuit 630 includes stimulation output circuit 232, a heart sounddetection circuit 634, and a stimulation control circuit 636.

Acoustic sensor 615 senses an acoustic signal indicative heart sounds.In one embodiment, acoustic sensor 615 includes an implantable acousticsensor. In one embodiment, acoustic sensor 615 includes anaccelerometer. In another embodiment, acoustic sensor 615 includes amicrophone. In one specific embodiment, acoustic sensor 615 is includedin implantable medical device 110. In another specific embodiment,acoustic sensor 615 is incorporated onto a lead connected to implantablemedical device 110.

Heart sound detection circuit 634 detects predetermined type heartsounds from the acoustic signal. Heart sound detection circuit 634includes one or more of a first heart sound (S1) detector to detect S1,a second heart sound (S2) detector to detect S2, a third heart sound(S3) detector to detect S3, and a fourth heart sound (S4) detector todetect S4. In one embodiment, the type of heart sounds to be detected isdetermined based on whether each particular type of heart sounds isconsistently recurring and reliably detectable in an individual patient.In one embodiment, cardiac event detection circuit 634 includes a signalprocessor such as signal processor 342 and an event detector such asevent detector 344. In one specific embodiment, heart sound detectioncircuit 634 includes a filter having a pass-band corresponding to afrequency range of the predetermined type heart sounds. In anotherspecific embodiment, heart sound detection circuit 634 includes a signalaveraging circuit to average the acoustic signal over a predeterminednumber of cardiac cycles before the detection of the predetermined typeheart sounds. In another specific embodiment, heart sound detectioncircuit 634 receives an activity signal indicative of the patient'sgross physical activity level and stops detecting heart sounds while theactivity signal exceeds a predetermined threshold activity level. Inanother embodiment, heart sound detection circuit 634 includes an S2detector and/or an S3 detector such as those discussed in U.S. patentapplication Ser. No. 10/746,853, “METHOD AND APPARATUS FOR THIRD HEARTSOUND DETECTION,” filed on Dec. 24, 2003, assigned to CardiacPacemakers, Inc., which is incorporated by reference in its entirety.

Stimulation control circuit 636 is a specific embodiment and includes asynchronization module 638. Synchronization module 638 synchronizes thedelivery of the neural stimulation pulses to the predetermined typeheart sounds. In one embodiment, stimulation control circuit 636includes elements corresponding to those of stimulation circuit 336,including offset interval generator 339 and pulse delivery controller340. Synchronization circuit 638 includes one or both of a continuoussynchronization module to synchronize the delivery of the neuralstimulation pulses to the predetermined type heart sound of each ofconsecutive cardiac cycles and a periodic synchronization module tosynchronize the delivery of the neural stimulation pulses to thepredetermined type heart sound of each of selected cardiac cycles on aperiodic basis. The offset interval generator produces an offsetinterval starting with the detected predetermined type heart sound. Thepulse delivery controller sends the pulse delivery signal to start adelivery of a burst of a plurality of neural stimulation pulses when theoffset interval expires. In one embodiment, the pulse deliverycontroller sends the pulse delivery signal after the detection of thepredetermined type heart sound for each of consecutive cardiac cycles.In another embodiment, the pulse delivery controller sends the pulsedelivery signal after the detection of the predetermined type heartsound for each of selected cardiac cycles according to a predeterminedpattern or schedule, such as on a periodic basis.

FIG. 7 is a block diagram illustrating an embodiment of a cardiaccycle-synchronized neural stimulation system 731, which is a specificembodiment of system 231 and uses a hemodynamic signal to synchronizeneural stimulation to cardiac cycles. System 731 includes a hemodynamicsensor 715 and a cardiac cycle-synchronized neural stimulation circuit730, which is a specific embodiment of cardiac cycle-synchronized neuralstimulation circuit 230. Cardiac cycle-synchronized neural stimulationcircuit 730 includes stimulation output circuit 232, a hemodynamic eventdetection circuit 734, and a stimulation control circuit 736.

Hemodynamic sensor 715 senses a hemodynamic signal indicative ofhemodynamic performance, such as a signal indicative of blood pressureor flow. In one embodiment, hemodynamic sensor 715 is an implantablehemodynamic sensor. In one embodiment, hemodynamic sensor 715 includes aDoppler echocardiographic transducer to sense a peripheral blood flow.In another embodiment, hemodynamic sensor 715 includes a pressure sensorto sense a central or peripheral blood pressure. In another embodiment,hemodynamic sensor 715 includes a pulse oximeter to sense an oximetrysignal, which is a plethysmographic signal indicative of blood flow.

Hemodynamic event detection circuit 734 detects predetermined typehemodynamic events from the hemodynamic signal. The hemodynamic eventscorrespond to a recurring feature of the cardiac cycle that is chosen tobe a timing reference to which the neural stimulation is synchronized.In one embodiment, hemodynamic event detection circuit 734 includes apeak detector that detects predetermined type peaks in the hemodynamicsignal. In one specific embodiment, the peak detector is a pressure peakdetector that detects predetermined type peaks in a blood pressuresignal. In another specific embodiment, the peak detector includes aflow peak detector that detects predetermined type peaks in a blood flowsignal. The predetermined type peaks are peaks indicative of acharacteristic event that occurs during each cardiac cycle. In anotherembodiment, cardiac cycle-synchronized neural stimulation circuit 730includes a derivative calculator to produce a derivative hemodynamicsignal by calculating a time derivative of the hemodynamic signal.Hemodynamic event detection circuit 734 detects the predetermined typehemodynamic event from the derivative hemodynamic signal. In oneembodiment, the peak detector detects predetermined type peaks in thederivative hemodynamic signal. In one specific embodiment, the peakdetector is a pressure change peak detector that detects predeterminedtype peaks in a derivative hemodynamic signal indicative of changes inthe blood pressure (e.g., dP/dt). In another specific embodiment, thepeak detector includes a flow change peak detector that detectspredetermined type peaks in a derivative hemodynamic signal indicativechanges in the blood flow.

Stimulation control circuit 736 is a specific embodiment and includes asynchronization module 738. Synchronization module 738 synchronizes thedelivery of the neural stimulation pulses to the predetermined typehemodynamic events. In one embodiment, stimulation control circuit 736includes elements corresponding to those of stimulation circuit 336,including offset interval generator 339 and pulse delivery controller340. Synchronization circuit 738 includes one or both of a continuoussynchronization module to synchronize the delivery of the neuralstimulation pulses to the predetermined type hemodynamic event of eachof consecutive cardiac cycles and a periodic synchronization module tosynchronize the delivery of the neural stimulation pulses to thepredetermined type hemodynamic event of each of selected cardiac cycleson a periodic basis. The offset interval generator produces an offsetinterval starting with each detected predetermined type hemodynamicevent. The pulse delivery controller sends the pulse delivery signal tostart a delivery of a burst of a plurality of neural stimulation pulseswhen the offset interval expires. In one embodiment, the pulse deliverycontroller sends the pulse delivery signal after the detection of thepredetermined type hemodynamic event for each of consecutive cardiaccycles. In another embodiment, the pulse delivery controller sends thepulse delivery signal after the detection of the predetermined typehemodynamic event for each of selected cardiac cycles according to apredetermined pattern or schedule, such as on a periodic basis.

FIG. 8 is a flow chart illustrating an embodiment of a method forsynchronizing neural stimulation to cardiac cycles. In one embodiment,the method is performed by cardiac cycle-synchronized neural stimulationsystem 231, including any of its specific embodiments or any combinationof its specific embodiments discussed above.

A reference signal is sensed at 800. The reference signal is indicativeof cardiac cycles each including a predetermined type timing referenceevent. In one embodiment, the reference signal is sensed using animplantable sensor placed external to the circulatory system. Examplesof the reference signal include a cardiac signal such as a subcutaneousECG signal, an acoustic signal indicative of heart sounds, and ahemodynamic signal such as a blood pressure or flow signal.

The predetermined type timing reference event is detected at 810. In oneembodiment, the reference signal is processed to allow or to facilitatethe detection of the predetermined type timing reference event. In onespecific embodiment, the predetermined type timing reference event isdetected based on the reference signal sensed over a single cardiaccycle. In another embodiment, the predetermined type timing referenceevent is detected based on the reference signal sensed over a pluralityof cardiac cycles. Examples of such processing include filtering,blanking unwanted activities from the reference signal, detecting anintermediate event having an approximately predictable timingrelationship with the predetermined type timing reference event, andaveraging the reference signal over a plurality of cardiac cycles.Examples of the predetermined type timing reference event include P-waveand R-wave detected from the cardiac signal such as the subcutaneous ECGsignal, a predetermined type heart sound from the acoustic signal, and apoint of peak amplitude or any other morphologically distinctive pointin the hemodynamic signal such as the pressure or flow signal.

A delivery of neural stimulation pulses is synchronized to thepredetermined type timing reference event at 820. In one embodiment, thedelivery of the neural stimulation pulses is synchronized to thepredetermined type timing reference event of each of consecutive cardiaccycles on a continuous basis. In another embodiment, the delivery of theneural stimulation pulses is synchronized to the predetermined typetiming reference event of each of selected cardiac cycles on a periodicbasis. In one embodiment, a burst of neural stimulation pulses isdelivered at the end of an offset interval starting with thepredetermined type timing reference event. In one embodiment, the burstof neural stimulation pulses is delivered after the predetermined typetiming reference event for each cardiac cycle of consecutive cardiaccycles. In another embodiment, the burst of neural stimulation pulses isdelivered after the predetermined type timing reference event for eachcardiac cycle of selected cardiac cycles according to a predeterminedpattern or schedule, such as on a period basis.

In one embodiment, the delivery of the neural stimulation pulses isfurther controlled by the patient's cardiac condition and/or activitylevel. The patient's cardiac rhythm and one or more cardiac parametersindicative of the cardiac functions are monitored. In one embodiment,the delivery of the neural stimulation pulses is controlled based on thecardiac rhythm. In response to a detected arrhythmia, the delivery ofthe neural stimulation pulses is withheld or adjusted. In anotherembodiment, the delivery of the neural stimulation pulses is adjusted oroptimized based on the one or more cardiac parameters. Examples of suchcardiac parameters include heart rate, atrioventricular intervals, andinterventricular intervals. The timing for the delivery of the neuralstimulation pulses is adjusted, for example, for a desirable heart rate,an atrioventricular interval corresponding to a desirable hemodynamicperformance, and/or a minimum interventricular interval.

It is to be understood that the above detailed description is intendedto be illustrative, and not restrictive. Other embodiments will beapparent to those of skill in the art upon reading and understanding theabove description. The scope of the invention should, therefore, bedetermined with reference to the appended claims, along with the fullscope of legal equivalents to which such claims are entitled.

1. A neural stimulation system coupled to a living subject having acirculatory system, the neural stimulation system comprising: astimulation output circuit to deliver neural stimulation pulses; aplurality of electrodes configured to sense a plurality of subcutaneouselectrocardiogram (ECG) vectors indicative of cardiac cycles eachincluding a predetermined type timing reference event, the plurality ofelectrodes configured for placement external to the circulatory system;a reference event detection circuit coupled to the plurality ofelectrodes, the reference event detection circuit adapted to detect thepredetermined type timing reference event using the plurality ofsubcutaneous ECG vectors; a cardiac parameter measurement circuitcoupled to the plurality of electrodes and adapted to measure anatrioventricular interval; a stimulation control circuit coupled to thestimulation output circuit and the reference event detection circuit andadapted to adjust delivery of neural stimulation pulses using themeasured atrioventricular interval, the stimulation control circuitincluding: an offset interval generator adapted to produce an offsetinterval starting with the predetermined type timing reference event;and a pulse delivery controller adapted to start a delivery of a burstof the neural stimulation pulses when the offset interval expires; andan implantable housing configured to contain at least the stimulationoutput circuit, the reference event detection circuit, the cardiacparameter measurement circuit, and the stimulation control circuit, theimplantable housing including a hermetically sealed can being anelectrode of the plurality of electrodes.
 2. The neural stimulationsystem of claim 1, wherein the reference event detection circuitcomprises a signal processor adapted to extract the predetermined typetiming reference event from the reference signal for each of the cardiaccycles.
 3. The neural stimulation system of claim 2, wherein thesynchronization module comprises a continuous synchronization moduleadapted to synchronize the delivery of the neural stimulation pulses tothe predetermined type timing reference event consecutively for each ofthe cardiac cycles.
 4. The neural stimulation system of claim 1, whereinthe reference event detection circuit comprises a signal processoradapted to extract the predetermined type timing reference event from asegment of the reference signal associated with a plurality of cardiaccycles.
 5. The neural stimulation system of claim 4, wherein thesynchronization module comprises a periodic synchronization moduleadapted to synchronize the delivery of the neural stimulation pulsesperiodically for a cardiac cycle of a predetermined number of thecardiac cycles.
 6. The neural stimulation system of claim 1, comprisinga header attached to the can, the header including connectors configuredto provide for electrical access to a circuit housed in the can, andwherein the plurality of electrodes comprises one or more electrodesincorporated onto the header.
 7. The neural stimulation system of claim6, wherein the plurality of electrodes comprises one or more electrodesincorporated onto the can and electrically insulated from the can. 8.The neural stimulation system of claim 6, wherein the reference eventdetection circuit comprises a P-wave detector to detect atrialdepolarizations (P-waves) from the subcutaneous ECG vectors.
 9. A neuralstimulation system, comprising: a stimulation output circuit to deliverneural stimulation pulses; implantable electrodes configured to sense asubcutaneous electrocardiogram (ECG) signal; a cardiac parametermeasurement circuit coupled to the implantable electrodes, the cardiacparameter measurement circuit adapted to measure one or more cardiacparameters including an atrioventricular interval from the subcutaneousECG signal; a cardiac event detection circuit coupled to the implantableelectrodes, the cardiac event detection circuit adapted to detectpredetermined type cardiac events from the subcutaneous ECG signal; astimulation control circuit coupled to the stimulation output circuit,the cardiac parameter measurement circuit, and the cardiac eventdetection circuit, the stimulation control circuit adapted to adjust thedelivery of the neural stimulation pulses based on the measured one ormore cardiac parameters including the atrioventricular interval andincluding a synchronization module adapted to synchronize the deliveryof the neural stimulation pulses to the predetermined type cardiacevents; and an implantable housing including a hermetically sealed canadapted to house the stimulation output circuit, the cardiac eventdetection circuit, and the stimulation control circuit, the canincluding at least one conductive portion made of electricallyconductive material; wherein the implantable electrodes include a canelectrode including the at least one conductive portion of the can. 10.The neural stimulation system of claim 9, wherein the stimulationcontrol circuit comprises an offset interval generator to produce anoffset interval starting with one of the detected predetermined typecardiac events and a pulse delivery controller adapted to start adelivery of a burst of a plurality of neural stimulation pulses when theoffset interval expires.
 11. The neural stimulation system of claim 9,wherein the cardiac event detection circuit comprises an R-wave detectorto detect ventricular depolarizations (R-waves).
 12. The neuralstimulation system of claim 9, wherein the cardiac event detectioncircuit comprises a P-wave detector to detect atrial depolarizations(P-waves).
 13. The neural stimulation system of claim 12, wherein theP-wave detector is adapted to detect ventricular depolarizations(R-waves) from the subcutaneous ECG vectors and generate a timinginterval upon detection of each of the R-waves, the P-waves eachestimated to occur at the end of the timing interval.
 14. The neuralstimulation system of claim 12, wherein the P-wave detector comprises asignal averaging circuit to average the subcutaneous ECG signal over aplurality of cardiac cycles.
 15. The neural stimulation system of claim9, further comprising an arrhythmia detection circuit to detect anarrhythmia from the subcutaneous ECG signal, and wherein the stimulationcontrol circuit is adapted to withhold or adjust the delivery of theneural stimulation pulses when the arrhythmia is detected.
 16. Theneural stimulation system of claim 9, comprising a header attached tothe can, the header including connectors configured to provide forelectrical access to a circuit housed in the can, and wherein theimplantable electrodes comprise one or more electrodes incorporated ontothe header.
 17. The neural stimulation system of claim 16, wherein theimplantable electrodes comprise one or more electrodes incorporated ontothe can and electrically insulated from the can.
 18. The neuralstimulation system of claim 17, wherein the one or more electrodes areincorporated onto the can and electrically insulated from the cancomprise a plurality of concentric electrodes.
 19. The neuralstimulation system of claim 18, wherein the plurality of concentricelectrodes comprises an outer electrode having a shape approaching acontour of the can.
 20. The neural stimulation system of claim 9,wherein the cardiac parameter measurement circuit is adapted to measurea heart rate, and wherein the stimulation control circuit is adapted toadjust the delivery of the neural stimulation pulses using the measuredheart rate.